16alpha, 17alpha-substituted methylene dioxy ethers of steroids of the pregnane series and method of preparing the same



United States Patent 16u,17a-SUBSTITUTED METHYLENE DIOXY ETHERS OF STEROIDS OF THE PREGNANE AND METHOD OF PREPARING THE Leland L. Smith, New City, N.Y., and Michael Marx,

Leonia, N.J., assignors to American Cyanamid Company, New York, N .Y., a corporation of Maine No Drawing. Filed Mar. 20, 1959, Ser. No. 800,640

'12 Claims. (Cl. 260-23955) This invention relates to new steroid compounds. More particularly, it relates to 16a,17a-substituted methylenedioxy ethers of steroids of the pregnane series and method of preparing the same.

In the past, it is known to prepare 16x,17a-isopropylidenedioxy pregnanes from the corresponding 16a,17adihydroxy pregnane [Journal of the Chemical Society, 4373, (1955)].

We have now found a new class of steroid esters which have high glucocorticoid activity. These esters can be illustrated by the following structural formula:

in which R is a member of the group consisting of hydrogen and lower alkanoyl radicals, R is a lower alkyl radical, R is a member of the group consisting of hydrogen and lower alkyl radicals, R is a member of the group consisting of and 0: groups, R is a member of the group consisting of hydrogen, halogen and methyl radicals, X is a member of the group consisting of hydrogen and halogen atoms and --C C is a member of the group consisting of -CHzCHz- --CH=CH -CHz-CH ower alkyl and lower alkyl groups.

The compounds of the present invention are insoluble in water and somewhat soluble in the usual organic solvents. They are generally crystalline solids having relatively high melting points.

The compounds of the present invention are prepared by the reaction of a vicinal cis-dihydroxy steroid having the following structure:

in which R, R R X and -C -C are as defined above, with an ortho ester having the formula in which R and R are as defined above. The reaction is preferably carried out by adding the steroid to the ortho ester and allowing the reaction to take place in the presence of a mineral acid. The reaction is usually carried out at a temperature within the range of from about 15 to about 60 C. It is usually complete within a period of from a few minutes to about an hour.

After the formation of the 16a,17a-cyclic ortho-ester on the steroid nucleus, other transformations can be made, such as conversion of the 2l-hydroxymethylene group into a lower alkanoyloxy-methylene group by reaction with a lower alkanoic acid anhydride or chloride.

Among the suitable reagents can be mentioned acetic.

anhydride, propionic anhydride, butyric anhydride, acetyl chloride, propionyl chloride and the like.

The 16a,l7a-cyclic ortho-esters of this invention display improved stability towards alkali in comparison with the ordinary 16a,2l-diesters of the steroids involved. Whereas alkaline conditions are sufficient to remove easily and completely the lfiocand 21-acetate ester groups, it is often possible to show that the cyclic ortho-esters of this invention are not completely hydrolyzed, even under extended hydrolysis conditions.

The starting steroids utilizable in the process of the present invention can be, for example, 9a-fluoro-1lfl,16u, 17a,2l-tetrahydroXy-l,4-pregnadiene-3,20-dione; 9a-fluo- 1'O-11ot,16ot,17a,21 tetrahydroxy 4 pregnene 3,20- dione; 1113,16u,17a,2l-tetrahydroxy-4-pregnene-3,ZO-dione; 9oc-ChlO1'O-l 13,1611,17a,21-tetra'hydroxy-4-pregnene- 3,20-dione; 9a-fiuoro 1113,160t,17oc,21 tetrahydroxy-6umethyl 1,4 pregnadiene-3,20-dione; 6a-chloro-11B,16u, 17a,21-tetrahydroxy-4-pregnene-3,20-dione; 6a,9a-difiuoro-11B,16 x,17a,21 tetrahydroxy 4 pregnene 3,20- dione; 11&16a,17a,2l-tetrahydroxy-Z-methyl-1,4-pregnadiene-3,20-dione, l1 8,16a,l7a,21-tetrahydroxy-1,4-pregnadiene-3,20-dione; 16a,17a,21-trihydroXy-1,4-preguadiene-3,1l,20-trione; t-ChlOI'O 11B,l6oz,17ot,21 tetrahydroxy-1,4-pregnadiene-3,ZO-dione; 2l-acetoxy-9a-chlorol15,16a,17a-trihydroXy-4-pregnene-3 ,20-dione; 9u-fluoro- 11B,16a,17oc,21 tetrahydroxy 20: methyl-4-pregnene- 3,20-dione; l1B,16a,16u,2l-tetrahydroxy 2oz methyl-4- pregnene-3,20-dione, and the like. The above steroids are described in Australian Patents 35,844/58 and 35,932/58 along with Belgian Patent No. 570,495. Some of the compounds are also described in US. Patents 2,838,546 and 2,838,548.

The other starting material, ortho ester, can be compounds such as ethyl ortho formate, ethyl ortho acetate, methyl ortho propionate, methyl ortho acetate, methyl ortho formate, and the like.

The compounds of the present invention are physiologically active possessing glucocorticoid and anti-inflamsilica gel.

7 crystals of the desired ortho-ester.

matory activity. They can be used systemically and topically in the treatment of rheumatoid arthritis, burns, allergies, psoriasis and other skin disorders.

In the present application, the term lower alkanoyl -is intended to cover derivatives of 'alkanoic acids having 1-6 carbon atoms. The term halogen covers bromine, chlorine, iodine and fluorine. The temperatures are on the centigrade scale unless otherwise indicated.

The following examples describe the present invention in greater particularity and are intended to be by way of illustration and not limitation.

EXAMPLE 1 16a,]7a-et/zoxymethyIidenediOxy-Qa-fluOrO-I1,3,21-dihydroxy-I ,4-pregnadiene-3,20-dine One gram of 9a-fiuoro-11B,16a,l7a,21-tetrahydroxy- 1,4-pregnadiene-3,20-dione, J. Am. Chem. Soc. 78, 5693 (1956), is slurried in 50 ml. of ethyl ortho-formate and 0.3 ml..of 70% perchloric acid is added. An immediate yellow color appears and the solids dissolve. The colored solution is neutralized with 8 ml. of saturated aqueous sodium bicarbonate solution, at which point the deep color diminishes, and inorganic salts precipitate. The

solvent layer is decanted from the precipitate and concentrated under reduced pressure to a gum. The gum is dissolved in chloroform, the chloroform solution dried over anhydrous magnesium sulfate and adsorbed onto Elution of the steroid from the silica gel is accomplished with ethyl acetate; the eluates evaporated yields a residue which is crystallized from methylene chloride. The product obtained is a mixture of two components as evidenced by paper chromatograms. Re chromatography on silica gel yields the ester in the chloroform/ethyl acetate (80:20) eluates. Recrystallization from acetone/petroleum ether yields 545 mg. of crystals.

A 33? 239 my. (615,170; [a] 54-121.? (0.5% in MeOH)) EXAMPLE 2 16u,17u- (I-ethoxyethylidenedioxy)-9a-flu0r0-11;3,21-

dihy droxy-I ,4-pregnadiene-3,20-di0ne One gram of 9a-fluoro-l1B,l6a,l7a,2l-tetrahydroxy- 1,4-pregnadiene-3,ZO-dione is suspended in 50 ml. of ethyl ortho-acetate and 0.30 ml. of 70% perchloric acid is added. After 30 minutes shaking the mixture is neutralized with 8 ml. of saturated aqueous sodium bicarbonate solution and 30 ml. of water is added. The mixture is concentrated under reduced pressure until most of the organic solvent has been removed, and the resulting concentrate is extracted with methylene chloride. The dried methylene chloride extracts are decolorized with activated charcoal, filtered, and evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and adsorbed onto silica gel. Elution from silica gel is accomplished with chloroform containing 20% ethyl acetate. The eluates are concentrated to dryness under reduced pressure and the residue is crystallized from acetone/petroleum ether, yielding the crystalline ortho-ester. A 238 my. (15,150).

EXAMPLE 3 One gram of 9a-fiuoro-l15,16a,17a,2l tetrahydroxy- 1,4-pregnadiene-3,20-dione is slurried in 3.0 ml. of methyl ortho-formate and 0.30 ml. of 70% perchloric acid is added. A deep red coloration is produced. After ten minutes the reaction mixture is neutralized with saturated aqueous sodium bicarbonate solution (8 ml.), and the resulting solids are filtered. The filtrate is diluted with 20 ml. of water and concentrated under reduced pressure to remove the organic solvent. From the aqueous mixture a gum is recovered which yields 515 mg. of [11:15 +1278; A

4 EXAMPLE 4 One gram of 9a-fiuoro-11B,16a,17 x,2l-tetrahydroxy- 1,4-pregnadiene-3,20-dione is slurried in 30 ml. of methyl ortho-acetate and 0.30 ml. of 70% perchloric acid is added. After working up in the usual way, the pure ortho esteris obtained. [aJ +122.9; A 238 mp. (615,400).

EXAMPLE 5 .16a,17a-(1-methoxypropylidenedioxy)-9a-flu0r0-1l[3,21- dihydroxy-I ,4 -pregnadiene-3 ,20-dione To a suspension of 750 mg. of 9a-fiu0r0-11/3,16a,'17a, 2l-tetrahydroxy-1,4epregnadiene-3,ZO-dione in 15 ml. of methyl ortho-propionate is added 0.20 ml. of 70% perchloric acid. After neutralization and isolation in the usual manner, the ortho-ester is recovered. After recrystallization from petroleum ether/acetone the pure orthoester is obtained. [al +111.0; A 238 mp. -(e15,1 50).

EXAMPLE 6 16 x,17a-(I-methoxyethylidenedioxy)-9a-flu0r0-11fl,21- dihydroxy-4-pregnene-3,20-dione To a suspension of 1.0 g. of 9a-fluoro-11 3,16u,17a,21- tetrahydroxy-4-pregnene-3,20-dione, J. Am. Soc. 78, 5693 1956), in 50 ml. of methyl ortho-acetate is added 0.30 ml. of 70% perchloric acid. After ten minutes the reaction mixture is processed in the usual way to yield the pure ortho-ester.

EXAMPLE 7 ;,1 7a-ethoxymezhylidenedioxy-I1fi,21-dihydroxy4- pregnene-3,20-dione One gram of 16a-hydroxycortisone, J. Am. Chem. Soc. 78, 1909 (1956), is suspended in 50 ml. of ethyl orthoformate and 0.30 ml. of concentrated hydrochloric acid is added. After thirty minutes the reaction mixture is neutralized and extracted in the usual way. After chromatography the pure ortho-ester is isolated.

EXAMPLE 9 9a-chI0r0-16aJ 7a-eth0xymethylidenedi0xy-11fi,21-dihydroxy-4-pregnene-3,20-di0ne To a suspension of 0.5 g. of 9u-chloro-16a-hydroxyhydrocortisone, J. Am. Chem. Soc. 78, 5693 (1956),in 30 ml. of ethyl ortho-formate is added 0.15 ml. of perchloric acid. After fifteen minutes the mixture is neutralized with 4 ml. of saturated aqueous sodium bicarbonate solution and the mixture processed as described in the preceding examples to give the pure ortho-ester.

EXAMPLE 10 21 acetoxy-16a,17a-ethoxymethylidenedioxy-h-fluoro- 1 1 fl-hydroxy-I ,4-pregnadiene-3,20-diane One hundred milligrams of 16a,17u-ethoxymethylidenedioxy 9ix-fluoro-l15,21-dihydroxy-1,4-pregnadiene- 3,20-dione from Example 1 is dissolved in 0.5 ml. 'of dry pyridine and 0.1 m1. of acetic anhydride -is added. After standing over night, the reaction is terminated by adding methanol. The solvents are removed under reduced pressure and fresh methanol and toluene are added and evaporation repeated until the odor of pyridine is removed. The residue so obtained is crystallized from acetone-petroleum ether and is homogeneous on paper chromatograrns. 7t,,,,,,, 238 m (45,620).

EXAMPLE 11 160:,170: ethwtymethylidenedioxy-9a-fluora-I1B,21-dihydroxy-6a-m ethyl-1 ,4-pregnadien e-3,20-dione One hundred milligrams of 9u-fiuoro 1lfl,16a,17a, 21- tetrahydroxy 6u-methyl-l,4-pregnadiene-3,20-dione (U.S. Patent 2,831,003) is suspended in ml. of ethyl orthoformate and a few drops of 70% perchloric acid is added. The colored solution so formed is then neutralized with saturated sodium bicarbonate solution and filtered from insolubles. The filtrate is concentrated in vacuum to remove organic solvent, and the precipitated solids are recovered and crystallized from acetone/petroleum ether. After several recrystallizations the pure oa-methyltriamcinolone 16u,17a-ethyl ortho-formate derivative is obtained. The compound is characterized by infrared spectra as an ortho-ester and contains bands distinctive of the A -3-ketone grouping.

EXAMPLE l2 EXAMPLE 13 611,90: difluoro 160a,]7a-meth0xymethylidenedioxy-I1p, 21-dihydroxy-4-pregnene-3,20-di0ne One gram of 6a,9a-difluoro-16a-hydroxy-hydrocortisone (US. Patent 2,838,548) is slurried in 30 ml. of methyl ortho-formate and 0.3 ml. of 70% perchloric acid is added. The solution so formed is neutralized with bicarbonate and worked up in the usual manner according to the other examples. After chromatography on silica gel and several recrystallizations the pure ortho-ester is obtained.

EXAMPLE 14 160:,170; ethoxymethylidenedioxy 113,21 dihydroxy 2 a-meth yl-I ,4-pregnadiene-3 ,ZO-dione One gram of 2-methyl-l6u-hydroxyprednisolone, I. Am. Chem. Soc. 81, 1696 (1959), is slurried in 50 ml. of ethyl ortho-formate and 0.3 ml. of 70% perchloric acid is added. After a few minutes the solution is processed in the usual manner to obtain a crude solid product, which after chromatography on silica gel and several recrystallizations from acetone with petroleum ether, has constant properties characteristic of the 16a,17a-ortho-ester.

We claim:

1. A compound having the formula 6 in which R is a member of the group consisting of hydrogen and lower alkanoyl radicals, R is a lower alkyl radical, R is a member of the group consisting of hydrogen and lower alkyl radicals, R is a member of the group consisting of HO(B)\ and 0: group, R is a member of the group consisting of hydrogen, halogen and methyl radicals, X is a member of the group consisting of hydrogen and halogen atoms and -C C is a member of the group consisting of CH CH CH=CH-- OH20H ower alkyl and -CH=C- ower alkyl groups.

in which R is a member of the group consisting of hydrogen and lower alkanoyl radicals, R is a lower alkyl radical, R is a member of the group consisting of hydrogen and lower alkyl radicals, R is a member of the group consisting of and group, R is a member of the group consisting of hydrogen, halogen and methyl radicals and is a member of the group consisting of -CH --CH --CH=CH--,

-cH,-pH

ower alkyl and l lower alkyl groups, which comprises contacting the corresponding 16a,l7a-dihydroxy steroid with an ortho-ester having the formula R C(OR) in which R and R are as defined above at a temperature within the range of about ester is ethyl ortho-formate.

11. The process according to-claim 8 where the ortho- -ester is methyl ortho-forrnate.

12. The process according to claim 8 where the orthoester is ethyl ortho-acetate.

8 References :Citedin the file .oflthis patent UNITED STATES PATENTS 2,584,271 Huffman Feb. 5, 1952 2,736,732 Knowles Feb. 28, 1956 2,831,003 Thomas. ,Apr. 15, 1958 OTHER REFERENCES Ellis et al.: J. Chem. Soc. (December 1955), pages 4383-4388.

Fried et al.: I. Am. Chem. Soc.,'vol. 80 (May v5, 1958), pages 2338 and 2339.

UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,966,486 December 27, 1960 Leland L. Smith et al. It is hereby certified that error appears in the above numbered patent requiring correct1on and that the sand Letters Patent should read as corrected below.

Column 1, lines 35 to 41, column 5, lines 70 to 75, and column 6, lines 49 to 55, the lower left-hand portion of the formulas, each occurrence, should appear as shown below instead of as m the patent:

coltlmr 2, lines 3 to 15, the formula should appear as shown below instead of as in the pa n L-OH H --OH column 6, lines 15 to 18, the right-hand portion of the formula should appear as shown below instead of as in the patent:

r war-on- (2a) lbwer alkyl Signed and sealed this 27th day of June 1961.

Attestz ERNEST W. SVVIDEB, DAVID L. LADD,

q Attesti/ng Oflicer. Commissioner of Patents. 

1. A COMPOUND HAVING THE FORMULA
 8. A METHOD OF PREPARING COMPOUNDS HAVING THE GENERAL FORMULA 